Major bottlenecks for therapeutic application of polypeptides are their limited solubility, in vivo stability, short serum half-life and fast clearance from the bloodstream.
Different approaches are reported to address this. One approach to improve PK/stability and biophysical behavior of therapeutic polypeptides is to fuse them to entities which stabilized the polypeptide, keep it in solution, and extend its half-life. Examples of such entities are human serum albumin or human immunoglobulin Fc-regions. Another approach to improve PK/stability and biophysical behavior of therapeutic polypeptides, is the chemical or enzymatic conjugation to polymers, for example by PEGylation or HESylation.
U.S. Pat. No. 5,804,371 reports hapten-labeled peptides and their use in an immunological method of detection. A digoxigenin-labeled peptide (Bradykinin) and its application to chemiluminoenzyme immunoassay of Bradykinin in inflamed tissues are reported by Decarie A., et al. (Peptides 15 (1994) 511-518).
In WO 2004/065569 multi-functional antibodies are reported.
In WO 2011/003780 bi-specific digoxigenin binding antibodies are reported.
In WO 2012/093068 a pharmaceutical composition of a complex of an anti-DIG antibody and digoxigenin that is conjugated to a peptide is reported.
In WO 2014/006124 covalent complexes of anti-hapten antibodies and a haptenylated payload are reported.
Monoclonal antibodies have vast therapeutic potential for treatment of neurological or central nervous system (CNS) diseases, but their passage into the brain is restricted by the blood-brain-barrier (BBB). Past studies have shown that a very small percentage (approximately 0.1%) of an IgG circulating in the bloodstream crosses through the BBB into the CNS (Felgenhauer, K., Klin. Wschr. 52 (1974) 1158-1164), where the CNS concentration of the antibody may be insufficient to permit a robust effect.
It has been reported that by defining the binding mode of an antibody or antibody fragment that specifically binds to a blood-brain-barrier receptor (BBBR) to be monovalent a BBB-shuttle module with BBB transcytosis properties can be obtained WO 2014/033074.
It has been reported that by using an antibody or antibody fragment that specifically binds to a BBBR with medium affinity a BBB-shuttle module with BBB transcytosis properties can be obtained WO 2012/075037.
It has been reported that by using an antibody or antibody fragment that has a specific ratio of EC50 values determined at different pH values a BBB-shuttle module with BBB transcytosis properties can be obtained WO 2012/143379.
Pardridge, W. M., reports the re-engineering of biopharmaceuticals for delivery to brain with molecular Trojan horses (Bioconjug. Chem. 19 (2008) 1327-1338). Receptor-mediated transport of drugs across the BBB is reported by Feng Ji-Ming et al. (Neurometh. 45 (2010) 15-34). Zhou, Q-H., et al. report the delivery of a peptide radiopharmaceutical to brain with an IgG-avidin fusion protein (Bioconjug. Chem. 22 (2011) 1611-1618). The study of the transcytosis of an anti-transferrin receptor antibody with a Fab′ cargo across the blood-brain barrier in mice is reported by Manich, G., et al. (Eur. J. Pharm. Sci. 49 (2013) 556-564).